How autophagy controls the intestinal epithelial barrier

References

• Peterson LW, Artis D. Intestinal epithelial cells: Regulators of barrier function and immune homeostasis. Nat Rev Immunol. 2014;143:141–153.
   PubMed Web of Science ®Google Scholar
• Barker N, Van Es JH, Kuipers J, et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature. 2007;449(7165):1003–1007.
   PubMed Web of Science ®Google Scholar
• Sato T, Van Es JH, Snippert HJ, et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469(7330):415–418.
   PubMed Web of Science ®Google Scholar
• Torres J, Mehandru S, Colombel JF, et al. Crohn’s disease. Lancet. 2017;389(10080):1741–1755.
   PubMed Web of Science ®Google Scholar
• Liu JZ, Van Sommeren S, Huang H, et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet. 2015;47(9):979–986.
   PubMed Web of Science ®Google Scholar
• Hampe J, Franke A, Rosenstiel P, et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211.
   PubMed Web of Science ®Google Scholar
• Parkes M, Barrett JC, Prescott NJ, et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet. 2007;39(7):830–832.
   PubMed Web of Science ®Google Scholar
• Rioux JD, Xavier RJ, Taylor KD, et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet. 2007;39(5):596–604.
   PubMed Web of Science ®Google Scholar
• Prescott NJ, Fisher SA, Franke A, et al. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn’s disease and is independent of CARD15 and IBD5. Gastroenterology. 2007;132(5):1665–1671.
   PubMed Web of Science ®Google Scholar
• Rufini S, Ciccacci C, Di Fusco D, et al. Autophagy and inflammatory bowel disease: Association between variants of the autophagy-related IRGM gene and susceptibility to Crohn’s disease. Dig Liver Dis. 2015;47(9):744–750.
   PubMedGoogle Scholar
• Henckaerts L, Cleynen I, Brinar M, et al. Genetic variation in the autophagy gene ULK1 and risk of Crohn’s disease. Inflamm Bowel Dis. 2011;17(6):1392–1397.
   PubMed Web of Science ®Google Scholar
• Barrett JC, Hansoul S, Nicolae DL, et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease. Nat Genet. 2008;40(8):955–962.
   PubMed Web of Science ®Google Scholar
• Hui KY, Fernandez-Hernandez H, Hu J, et al. Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med. 2018;10(423):1–13.
   Web of Science ®Google Scholar
• Rivas MA, Avila BE, Koskela J, et al. Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 2018;14(5):1–25.
   Web of Science ®Google Scholar
• Larabi A, Barnich N, Nguyen HTT. New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD. Available from Autophagy. 2020;161:38–51.
   PubMed Web of Science ®Google Scholar
• Kabat AM, Pott J, Maloy KJ. The mucosal immune system and its regulation by autophagy. Front Immunol. 2016;7:1–25.
   PubMed Web of Science ®Google Scholar
• Lassen KG, Xavier RJ. Mechanisms and function of autophagy in intestinal disease. Autophagy. 2018;142:216–220.
   PubMed Web of Science ®Google Scholar
• Kim S, Eun H, Jo E-K. Roles of autophagy-related genes in the pathogenesis of inflammatory bowel disease. Cells. 2019;8(1):1–24.
   Web of Science ®Google Scholar
• Haq S, Grondin J, Banskota S, et al. Autophagy: Roles in intestinal mucosal homeostasis and inflammation. J Biomed Sci. 2019;26(1):1–14.
   PubMedGoogle Scholar
• Wu Y, Tang L, Wang B, et al. The role of autophagy in maintaining intestinal mucosal barrier. J Cell Physiol. 2019;234(11):19406–19419.
   PubMed Web of Science ®Google Scholar
• Takeshige K, Baba M, Tsuboi S, et al. Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol. 1992;119(2):301–312.
   PubMed Web of Science ®Google Scholar
• Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28(4):170–185.
   PubMed Web of Science ®Google Scholar
• Sharma V, Verma S, Seranova E, et al. Selective autophagy and xenophagy in infection and disease. Front Cell Dev Biol. 2018;6:1–17.
   PubMed Web of Science ®Google Scholar
• Mizushima N. A brief history of autophagy from cell biology to physiology and disease. Nat Cell Bio. 2018;20(5):521–527.
   PubMed Web of Science ®Google Scholar
• Itakura E, Mizushima N. Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy. 2010;6(6):764–776.
   PubMed Web of Science ®Google Scholar
• Suzuki K, Kubota Y, Sekito T, et al. Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes to Cells. 2007;12(2):209–218.
   PubMed Web of Science ®Google Scholar
• Zachari M, Ganley IG. The mammalian ULK1 complex and autophagy initiation. Essays Biochem. 2017;61:585–596.
   PubMed Web of Science ®Google Scholar
• Kishi-Itakura C, Koyama-Honda I, Itakura E, et al. Ultrastructural analysis of autophagosome organization using mammalian autophagy-deficient cells. J Cell Sci. 2014;127(18):4089–4102.
   PubMed Web of Science ®Google Scholar
• Levine B, Kroemer G. Biological functions of autophagy genes: A disease perspective. Cell. 2019;176:11–42.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Yoshimori T, Ohsumi Y. The role of atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27(1):107–132.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Noda T, Yoshimori T, et al. A protein conjugation system essential for autophagy. Nature. 1998;395(6700):395–398.
   PubMed Web of Science ®Google Scholar
• Ichimura Y, Kirisako T, Takao T, et al. A ubiquitin-like system mediates protein lipidation. Nature. 2000;408(6811):488–492.
   PubMed Web of Science ®Google Scholar
• Kabeya Y, Mizushima N, Ueno T, et al. LC3, a mammalian homolog of yeast Apg8p, is localized in autophagosome membranes after processing. Embo J. 2000;19(21):5720–5728.
   PubMed Web of Science ®Google Scholar
• Blommaart EFC, Luiken JJFP, Blommaart PJE, et al. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem. 1995;270(5):2320–2326.
   PubMed Web of Science ®Google Scholar
• Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;1686:960–976.
   PubMed Web of Science ®Google Scholar
• Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of Ulk1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2010;331(6016):456–461.
   PubMed Web of Science ®Google Scholar
• Lin SC, Hardie DG. AMPK: Sensing glucose as well as cellular energy status. Cell Metab. 2018;272:299–313.
   PubMed Web of Science ®Google Scholar
• Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nat Cell Bio. 2013;15(7):713–720.
   PubMed Web of Science ®Google Scholar
• Hara K, Maruki Y, Long X, et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002;110(2):177–189.
   PubMed Web of Science ®Google Scholar
• Kim DH, Sarbassov DD, Ali SM, et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002;110(2):163–175.
   PubMed Web of Science ®Google Scholar
• Sarbassov DD, Ali SM, Kim D-H, et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004;14(14):1296–1302.
   PubMed Web of Science ®Google Scholar
• Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Bio. 2011;13(2):132–141.
   PubMed Web of Science ®Google Scholar
• Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004;36(6):585–595.
   PubMed Web of Science ®Google Scholar
• Meijer AJ, Codogno P. Autophagy: Regulation and role in disease. Crit Rev Clin Lab Sci. 2009;46:210–240.
   PubMed Web of Science ®Google Scholar
• Puertollano R, Ferguson SM, Brugarolas J, et al. The complex relationship between TFEB transcription factor phosphorylation and subcellular localization. Embo J. 2018;37(11):1–12.
   PubMed Web of Science ®Google Scholar
• Sardiello M, Palmieri M, Di Ronza A, et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325(5939):473–477.
   PubMed Web of Science ®Google Scholar
• Settembre C, Ballabio A. TFEB regulates autophagy: An integrated coordination of cellular degradation and recycling processes. Autophagy. 2011;7(11):1379–1381.
   PubMed Web of Science ®Google Scholar
• Settembre C, Di Malta C, Polito VA, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429–1433.
   PubMed Web of Science ®Google Scholar
• Inoki K, Li Y, Xu T, et al. Rheb GTpase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17(15):1829–1834.
   PubMed Web of Science ®Google Scholar
• Tee AR, Manning BD, Roux PP, et al. Tuberous Sclerosis Complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr Biol. 2003;13(15):1259–1268.
   PubMed Web of Science ®Google Scholar
• Castro AF, Rebhun JF, Clark GJ, et al. Rheb binds tuberous sclerosis complex 2 (TSC2) and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J Biol Chem. 2003;278(35):32493–32496.
   PubMed Web of Science ®Google Scholar
• Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov. 2012;11:709–730.
   PubMed Web of Science ®Google Scholar
• Martina JA, Diab HI, Lishu L, et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci Signal. 2014;7(309):1–16.
   Web of Science ®Google Scholar
• Palmieri M, Impey S, Kang H, et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet. 2011;20(19):3852–3866.
   PubMed Web of Science ®Google Scholar
• Yu X, Long YC, Shen HM. Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy. Autophagy. 2015;11(10):1711–1728.
   PubMed Web of Science ®Google Scholar
• Frankel LB, Lund AH. MicroRNA regulation of autophagy. Carcinogenesis. 2012;33(11):2018–2025.
   PubMed Web of Science ®Google Scholar
• Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–355.
   PubMed Web of Science ®Google Scholar
• Sorbara MT, Foerster EG, Tsalikis J, et al. Complement C3 drives autophagy-dependent restriction of cyto-invasive bacteria. Cell Host Microbe. 2018;23(5):644–652.
   PubMed Web of Science ®Google Scholar
• Travassos LH, Carneiro LAM, Ramjeet M, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol. 2010;11(1):55–62.
   PubMed Web of Science ®Google Scholar
• Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature. 2008;456:264–268.
   PubMed Web of Science ®Google Scholar
• Kuma A, Hatano M, Matsui M, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–1036.
   PubMed Web of Science ®Google Scholar
• Mizushima N, Levine B. Autophagy in development and differentiation. Nat Cell Bio. 2010;12(9):823–830.
   PubMed Web of Science ®Google Scholar
• Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456(7219):259–263.
   PubMed Web of Science ®Google Scholar
• Wittkopf N, Günther C, Martini E, et al. Lack of intestinal epithelial Atg7 affects Paneth cell granule formation but does not compromise immune homeostasis in the gut. Clin Dev Immunol. 2012;2012:1–9.
   Google Scholar
• Tschurtschenthaler M, Adolph TE, Ashcroft JW, et al. Defective ATG16L1-mediated removal of IRE1α drives Crohn’s disease-like ileitis. J Exp Med. 2017;214(2):401–422.
   PubMed Web of Science ®Google Scholar
• Benjamin JL, Sumpter R, Levine B, et al. Intestinal epithelial autophagy is essential for host defense against invasive bacteria. Cell Host Microbe. 2013;13(6):723–734.
   PubMed Web of Science ®Google Scholar
• Conway KL, Kuballa P, Song JH, et al. Atg16l1 is required for autophagy in intestinal epithelial cells and protection of mice from Salmonella infection. Gastroenterology. 2013;145(6):1347–1357.
   PubMed Web of Science ®Google Scholar
• Cadwell K, Patel KK, Maloney NS, et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell. 2010;141(7):1135–1145.
   PubMed Web of Science ®Google Scholar
• Adolph TE, Tomczak MF, Niederreiter L, et al. Paneth cells as a site of origin for intestinal inflammation. Nature. 2013;503(7475):272–276.
   PubMed Web of Science ®Google Scholar
• Cadwell K, Patel KK, Komatsu M, et al. A common role for Atg16L1, Atg5, and Atg7 in small intestinal Paneth cells and Crohn’s disease. Autophagy. 2009;5(2):250–252.
   PubMed Web of Science ®Google Scholar
• Liu B, Gulati AS, Cantillana V, et al. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2013;305(8):573–584.
   PubMed Web of Science ®Google Scholar
• Rogala AR, Schoenborn AA, Fee BE, et al. Environmental factors regulate Paneth cell phenotype and host susceptibility to intestinal inflammation in Irgm1-deficient mice. Dis Model Mech. 2018;11:1–12.
   Web of Science ®Google Scholar
• Zhang Q, Pan Y, Yan R, et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nat Immunol. 2015;16(9):918–926.
   PubMed Web of Science ®Google Scholar
• Lassen KG, Kuballa P, Conway KL, et al. Atg16L1 T300A variant decreases selective autophagy resulting in altered cytokine signaling and decreased antibacterial defense. Proc Natl Acad Sci U S A. 2014;111(21):7741–7746.
   PubMed Web of Science ®Google Scholar
• Gehart H, Clevers H. Tales from the crypt: New insights into intestinal stem cells. Nat Rev Gastroenterol Hepatol. 2019;161:19–34.
   PubMed Web of Science ®Google Scholar
• Asano J, Sato T, Ichinose S, et al. Intrinsic Autophagy is required for the maintenance of intestinal stem cells and for irradiation-induced intestinal regeneration. Cell Rep. 2017;20(5):1050–1060.
   PubMed Web of Science ®Google Scholar
• Levy A, Stedman A, Deutsch E, et al. Innate immune receptor NOD2 mediates LGR5 + intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation. Proc Natl Acad Sci U S A. 2020;117(4):1994–2003.
   PubMed Web of Science ®Google Scholar
• Kaser A, Lee AH, Franke A, et al. XBP1 Links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134(5):743–756.
   PubMed Web of Science ®Google Scholar
• Ravindran R, Loebbermann J, Nakaya HI, et al. The amino acid sensor GCN2 controls gut inflammation by inhibiting inflammasome activation. Nature. 2016;531(7595):523–527.
   PubMed Web of Science ®Google Scholar
• Kim SW, Ehrman J, Ahn MR, et al. Shear stress induces noncanonical autophagy in intestinal epithelial monolayers. Mol Biol Cell. 2017;28(22):3043–3056.
   PubMed Web of Science ®Google Scholar
• Ravanan P, Srikumar IF, Talwar P. Autophagy: The spotlight for cellular stress responses. Life Sci. 2017;188:53–67.
   PubMed Web of Science ®Google Scholar
• Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78 Cells Response Stress. 2019;226:156–163.
   Google Scholar
• Niederreiter L, Fritz TMJ, Adolph TE, et al. ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells. J Exp Med. 2013;210(10):2041–2056.
   PubMed Web of Science ®Google Scholar
• Heijmans J, Van Lidth De Jeude JF, Koo BK, et al. ER stress causes rapid loss of intestinal epithelial stemness through activation of the unfolded protein response. Cell Rep. 2013;3(4):1128–1139.
   PubMed Web of Science ®Google Scholar
• Murthy A, Li Y, Peng I, et al. A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3. Nature. 2014;506(7489):456–462.
   PubMed Web of Science ®Google Scholar
• Deuring JJ, Fuhler GM, Konstantinov SR, et al. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn’s disease. Gut. 2014;63(7):1081–1091.
   PubMed Web of Science ®Google Scholar
• Tang HW, Liao HM, Peng WH, et al. Atg9 interacts with dTRAF2/TRAF6 to regulate oxidative stress-induced JNK activation and autophagy induction. Dev Cell. 2013;27(5):489–503.
   PubMed Web of Science ®Google Scholar
• Rodríguez-Colman MJ, Schewe M, Meerlo M, et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature. 2017;543(7645):424–427.
   PubMed Web of Science ®Google Scholar
• Khaloian S, Rath E, Hammoudi N, et al. Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn’s disease recurrence. Gut. 2020;0:1–13.
   Web of Science ®Google Scholar
• Berger E, Rath E, Yuan D, et al. Mitochondrial function controls intestinal epithelial stemness and proliferation. Nat Commun. 2016;7(1):1–17.
   Google Scholar
• Patel KK, Miyoshi H, Beatty WL, et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. Embo J. 2013;32(24):3130–3144.
   PubMed Web of Science ®Google Scholar
• Wlodarska M, Thaiss CA, Nowarski R, et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell. 2014;156(5):1045–1059.
   PubMed Web of Science ®Google Scholar
• O’Brien LE, Soliman SS, Li X, et al. Altered Modes of Stem Cell Division Drive Adaptive Intestinal Growth. Cell. 2011;147(3):603–614.
   PubMed Web of Science ®Google Scholar
• Igarashi M, Guarente L. mTORC1 and SIRT1 Cooperate to Foster Expansion of Gut Adult Stem Cells during Calorie Restriction. Cell. 2016;1662:436–450.
   PubMed Web of Science ®Google Scholar
• Yilmaz ÖH, Katajisto P, Lamming DW, et al. MTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature. 2012;486(7404):490–495.
   PubMed Web of Science ®Google Scholar
• Cosin-Roger J, Simmen S, Melhem H, et al. Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation. Nat Commun. 2017;8(1):1–13.
   PubMedGoogle Scholar
• Doherty J, Baehrecke EH. Life, death and autophagy. Nat Cell Bio. 2018;20(10):1110–1117.
   PubMed Web of Science ®Google Scholar
• Matsuzawa-Ishimoto Y, Shono Y, Gomez LE, et al. Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J Exp Med. 2017;214(12):3687–3705.
   PubMed Web of Science ®Google Scholar
• Burger E, Araujo A, López-Yglesias A, et al. Loss of Paneth Cell Autophagy Causes Acute Susceptibility to Toxoplasma gondii-Mediated Inflammation. Cell Host Microbe. 2018;23(2):177–190.
   PubMed Web of Science ®Google Scholar
• Pott J, Kabat AM, Maloy KJ. Intestinal Epithelial Cell Autophagy Is Required to Protect against TNF-Induced Apoptosis during Chronic Colitis in Mice. Cell Host Microbe. 2018;232:191–202.
   PubMed Web of Science ®Google Scholar
• Zhu X, Messer JS, Wang Y, et al. Cytosolic HMGB1 controls the cellular autophagy/apoptosis checkpoint during inflammation. J Clin Invest. 2015;125(3):1098–1110.
   PubMed Web of Science ®Google Scholar
• Xie Y, Zhao Y, Shi L, et al. Gut epithelial TSC1/mTOR controls RIPK3-dependent necroptosis in intestinal inflammation and cancer. J Clin Invest. 2020;130(4):2111–2128.
   PubMed Web of Science ®Google Scholar
• Aden K, Tran F, Ito G, et al. ATG16L1 orchestrates interleukin-22 signaling in the intestinal epithelium via cGAS-STING. J Exp Med. 2018;215(11):2868–2886.
   PubMed Web of Science ®Google Scholar
• Tang D, Kang R, Livesey KM, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190(5):881–892.
   PubMed Web of Science ®Google Scholar
• Jung H, Leal-Ekman JS, Lu Q, et al. Atg14 protects the intestinal epithelium from TNF-triggered villus atrophy. Autophagy. 2019;15(11):1990–2001.
   PubMed Web of Science ®Google Scholar
• Trentesaux C, Fraudeau M, Luana C, et al. Essential role for autophagy protein ATG7 in the maintenance of intestinal stem cell integrity. Proc Natl Acad Sci. 2020;117(20):1–11.
   Web of Science ®Google Scholar
• Buckley A, Turner JR. Cell biology of tight junction barrier regulation and mucosal disease. Cold Spring Harb Perspect Biol. 2018;10:1–16.
   Web of Science ®Google Scholar
• Hu CAA, Hou Y, Yi D, et al. Autophagy and tight junction proteins in the intestine and intestinal diseases. Anim Nutr. 2015;1(3):123–127.
   PubMedGoogle Scholar
• Nighot PK, Hu CAA, Ma TY. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. J Biol Chem. 2015;290(11):7234–7246.
   PubMed Web of Science ®Google Scholar
• Zhang C, Yan J, Xiao Y, et al. Inhibition of autophagic degradation process contributes to claudin-2 expression increase and epithelial tight junction dysfunction in TNF-α treated cell monolayers. Int J Mol Sci. 2017;18:1–13.
   Web of Science ®Google Scholar
• Wen JK, Wang YT, Chan CC, et al. Atg9 antagonizes TOR signaling to regulate intestinal cell growth and epithelial homeostasis in Drosophila. Elife. 2017;6:1–22.
   Web of Science ®Google Scholar
• Wong M, Ganapathy AS, Suchanec E, et al. Intestinal epithelial tight junction barrier regulation by autophagy-related protein ATG6/beclin 1. Am J Physiol Cell Physiol. 2019;316(5):753–765.
   PubMed Web of Science ®Google Scholar
• Strisciuglio C, Duijvestein M, Verhaar AP, et al. Impaired autophagy leads to abnormal dendritic cell-epithelial cell interactions. J Crohn’s Colitis. 2013;7(7):534–541.
   Google Scholar
• Ravikumar B, Sarkar S, Davies JE, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90(4):1383–1435.
   PubMed Web of Science ®Google Scholar
• Sun Q, Fan J, Billiar TR, et al. Inflammasome and autophagy regulation: A two-way street. Mol Med. 2017;23(1):188–195.
   PubMedGoogle Scholar
• Guan Y, Zhang L, Li X, et al. Repression of mammalian target of rapamycin complex 1 inhibits intestinal regeneration in acute inflammatory bowel disease models. J Immunol. 2015;195(1):339–346.
   PubMed Web of Science ®Google Scholar
• Gutiérrez-Martínez IZ, Rubio JF, Piedra-Quintero ZL, et al. mTORC1 prevents epithelial damage during inflammation and inhibits colitis-associated colorectal cancer development. Transl Oncol. 2019;12(1):24–35.
   PubMed Web of Science ®Google Scholar
• Sampson LL, Davis AK, Grogg MW, et al. MTOR disruption causes intestinal epithelial cell defects and intestinal atrophy postinjury in mice. Faseb J. 2016;30(3):1263–1275.
   PubMed Web of Science ®Google Scholar
• Zhou M, Xu W, Wang J, et al. Boosting mTOR-dependent autophagy via upstream TLR4-MyD88-MAPK signalling and downstream NF-κB pathway quenches intestinal inflammation and oxidative stress injury. EBioMedicine. 2018;35:345–360.
   PubMed Web of Science ®Google Scholar
• Murano T, Najibi M, Paulus GLC, et al. Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo. Sci Rep. 2017;7(1):1–13.
   PubMedGoogle Scholar
• Fan X, Liang Q, Lian T, et al. Rapamycin preserves gut homeostasis during Drosophila aging. Oncotarget. 2015;6(34):35274–35283.
   PubMedGoogle Scholar
• Na HJ, Pyo JH, Jeon HJ, et al. Deficiency of Atg6 impairs beneficial effect of metformin on intestinal stem cell aging in Drosophila. Biochem Biophys Res Commun. 2018;498(1):18–24.
   PubMed Web of Science ®Google Scholar
• Nagy P, Sándor GO, Juhász G. Autophagy maintains stem cells and intestinal homeostasis in Drosophila. Sci Rep. 2018;8(1):1–9.
   PubMedGoogle Scholar
• Guo T, Nan Z, Miao C, et al. The autophagy-related gene Atg101 in Drosophila regulates both neuron and midgut homeostasis. J Biol Chem. 2019;294(14):5666–5676.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Fernandez IA, Qi Y, Jasper H. Loss of a proteostatic checkpoint in intestinal stem cells contributes to age-related epithelial dysfunction. Nat Commun. 2019;10:1–15.
   PubMed Web of Science ®Google Scholar
• Zhang P, Holowatyj AN, Roy T, et al. An SH3PX1-dependent endocytosis-autophagy network restrains intestinal stem cell proliferation by counteracting EGFR-ERK signaling. Dev Cell. 2019;49(4):574–589.e5.
   PubMed Web of Science ®Google Scholar
• Mihaylova MM, Cheng CW, Cao AQ, et al. Fasting activates Fatty acid oxidation to enhance intestinal stem cell function during homeostasis and aging. Cell Stem Cell. 2018;22:769–778.e4.
   PubMed Web of Science ®Google Scholar
• He D, Wu H, Xiang J, et al. Gut stem cell aging is driven by mTORC1 via a p38 MAPK-p53 pathway. Nat Commun. 2020;11(1):1–13.
   PubMed Web of Science ®Google Scholar
• Nguyen HTT, Dalmasso G, Müller S, et al. Crohn’s disease-associated adherent invasive Escherichia coli modulate levels of microRNAs in intestinal epithelial cells to reduce autophagy. Gastroenterology. 2014;146(2):508–519.
   PubMed Web of Science ®Google Scholar
• Lapaquette P, Glasser AL, Huett A, et al. Crohn’s disease-associated adherent-invasive E. coli are selectively favoured by impaired autophagy to replicate intracellularly. Cell Microbiol. 2010;12:99–113.
   PubMed Web of Science ®Google Scholar
• Torchinsky MB, Garaude J, Martin AP, et al. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature. 2009;458(7234):78–82.
   PubMed Web of Science ®Google Scholar
• Marchiando AM, Ramanan D, Ding Y, et al. A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe. 2013;14(2):216–224.
   PubMed Web of Science ®Google Scholar
• Martin PK, Marchiando A, Xu R, et al. Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota. Nat Microbiol. 2018;3(10):1131–1141.
   PubMed Web of Science ®Google Scholar
• Wang C, Mendonsa GR, Symington JW, et al. Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo. Proc Natl Acad Sci U S A. 2012;109(27):11008–11013.
   PubMed Web of Science ®Google Scholar
• Sorbara MT, Ellison LK, Ramjeet M, et al. The protein ATG16L1 suppresses inflammatory cytokines induced by the intracellular sensors Nod1 and Nod2 in an autophagy-independent manner. Immunity. 2013;39(5):858–873.
   PubMed Web of Science ®Google Scholar
• Cabrera S, FernÁndez ÁF, Mariño G, et al. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis. Autophagy. 2013;9(8):1188–1200.
   PubMed Web of Science ®Google Scholar
• Bel S, Pendse M, Wang Y, et al. Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science. 2017;357(6355):1047–1052.
   PubMed Web of Science ®Google Scholar
• Liu X, Qin H, Xu J. The role of autophagy in the pathogenesis of systemic lupus erythematosus. Int Immunopharmacol. 2016;40:351–361.
   PubMed Web of Science ®Google Scholar
• Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet. 2010;42(12):1118–1125.
   PubMed Web of Science ®Google Scholar
• Lévy J, Cacheux W, Bara MA, et al. Intestinal inhibition of Atg7 prevents tumour initiation through a microbiome-influenced immune response and suppresses tumour growth. Nat Cell Bio. 2015;17(8):1062–1073.
   PubMed Web of Science ®Google Scholar
• Mokarram P, Albokashy M, Zarghooni M, et al. New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. Autophagy. 2017;13(5):781–819.
   PubMed Web of Science ®Google Scholar
• Villella VR, Esposito S, Ferrari E, et al. Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis. Cell Death Dis. 2019;10(4):1–11.
   Google Scholar
• De Stefano D, Villella VR, Esposito S, et al. Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation. Autophagy. 2014;10(11):2053–2074.
   PubMed Web of Science ®Google Scholar
• Hugot J, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibilty to Crohn’s disease. Nature. 2001;411(6837):599–603.
   PubMed Web of Science ®Google Scholar
• Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411(6837):603–606.
   PubMed Web of Science ®Google Scholar
• Vermeire S. NOD2/CARD15: Relevance in clinical practice. Best Pract Res Clin Gastroenterol. 2004;18(3):569–575.
   PubMed Web of Science ®Google Scholar
• Travassos LH, Carneiro LAM, Girardin S, et al. Nod proteins link bacterial sensing and autophagy. Autophagy. 2010;6(3):409–411.
   PubMed Web of Science ®Google Scholar
• Samie M, Lim J, Verschueren E, et al. Selective autophagy of the adaptor TRIF regulates innate inflammatory signaling article. Nat Immunol. 2018;19(3):246–254.
   PubMed Web of Science ®Google Scholar
• Ng SC, Tsoi KKF, Kamm MA, et al. Genetics of inflammatory bowel disease in Asia: Systematic review and meta-analysis. Inflamm Bowel Dis. 2012;18(6):1164–1176.
   PubMed Web of Science ®Google Scholar
• Liu TC, Naito T, Liu Z, et al. LRRK2 but not ATG16L1 is associated with Paneth cell defect in Japanese Crohn’s disease patients. JCI Insight. 2017;2(6):1–14.
   Web of Science ®Google Scholar
• Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119–124.
   PubMed Web of Science ®Google Scholar
• McCarroll SA, Huett A, Kuballa P, et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn’s disease. Nat Genet. 2008;40(9):1107–1112.
   PubMed Web of Science ®Google Scholar
• Manzoni C, Mamais A, Roosen DA, et al. MTOR independent regulation of macroautophagy by Leucine Rich Repeat Kinase 2 via Beclin-1. Sci Rep. 2016;6(1):1–10.
   PubMedGoogle Scholar
• Mak WY, Zhao M, Ng SC, et al. The epidemiology of inflammatory bowel disease: East meets west. J Gastroenterol Hepatol. 2020;35(3):380–389.
   PubMed Web of Science ®Google Scholar
• Brant SR, Okou DT, Simpson CL, et al. Genome-wide association study identifies African-specific susceptibility loci in African Americans with inflammatory bowel disease. Gastroenterology. 2017;152(1):2082–2083.
   PubMed Web of Science ®Google Scholar
• Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14(2):89–103.
   PubMed Web of Science ®Google Scholar
• Grimm WA, Messer JS, Murphy SF, et al. The Thr300Ala variant in ATG16L1 is associated with improved survival in human colorectal cancer and enhanced production of type I interferon. Gut. 2016;65(3):456–464.
   PubMed Web of Science ®Google Scholar
• Nicoli ER, Dumitrescu T, Uscatu CD, et al. Determination of autophagy gene ATG16L1 polymorphism in human colorectal cancer. Rom J Morphol Embryol. 2014;55:57–62.
   PubMed Web of Science ®Google Scholar
• Lucas C, Salesse L, Hoang MHT, et al. Autophagy of intestinal epithelial cells inhibits colorectal carcinogenesis induced by colibactin-producing Escherichia coli in ApcMin/+ mice. Gastroenterology. 2020;158(5):1373–1388.
   PubMed Web of Science ®Google Scholar
• Wang L, Wang Y, Lu Y, et al. Heterozygous deletion of ATG5 in Apc Min/+ mice promotes intestinal adenoma growth and enhances the antitumor efficacy of interferon-gamma. Cancer Biol Ther. 2015;16(3):383–391.
   PubMed Web of Science ®Google Scholar
• Huo HZ, Zhou ZY, Wang B, et al. Dramatic suppression of colorectal cancer cell growth by the dual mTORC1 and mTORC2 inhibitor AZD-2014. Biochem Biophys Res Commun. 2014;443(2):406–412.
   PubMed Web of Science ®Google Scholar
• Koustas E, Karamouzis MV, Mihailidou C, et al. Co-targeting of EGFR and autophagy signaling is an emerging treatment strategy in metastatic colorectal cancer. Cancer Lett. 2017;396:94–102.
   PubMed Web of Science ®Google Scholar
• Wu S, Zhang YG, Lu R, et al. Intestinal epithelial vitamin D receptor deletion leads to defective autophagy in colitis. Gut. 2015;64(7):1082–1094.
   PubMed Web of Science ®Google Scholar
• Liu TC, Kern JT, VanDussen KL, et al. Interaction between smoking and ATG16L1T300A triggers Paneth cell defects in Crohn’s disease. J Clin Invest. 2018;128(11):5110–5122.
   PubMed Web of Science ®Google Scholar
• Chang SY, Lee SN, Yang JY, et al. Autophagy controls an intrinsic host defense to bacteria by promoting epithelial cell survival: A murine model. PLoS One. 2013;8(11):1–12.
   Web of Science ®Google Scholar
• Inoue J, Nishiumi S, Fujishima Y, et al. Autophagy in the intestinal epithelium regulates Citrobacter rodentium infection. Arch Biochem Biophys. 2012;521(1–2):95–101.
   PubMed Web of Science ®Google Scholar
• Diamanti MA, Gupta J, Bennecke M, et al. IKKα controls ATG16L1 degradation to prevent ER stress during inflammation. J Exp Med. 2017;214(2):423–437.
   PubMed Web of Science ®Google Scholar
• Barron L, Sun RC, Aladegbami B, et al. Intestinal epithelial-specific mTORC1 activation enhances intestinal adaptation after small bowel resection. Cmgh. 2017;3(2):231–244.
   Google Scholar
• Huang L, Zhang D, Han W, et al. High-mobility group box-1 inhibition stabilizes intestinal permeability through tight junctions in experimental acute necrotizing pancreatitis. Inflamm Res. 2019;68(8):677–689.
   PubMed Web of Science ®Google Scholar